Psoriasis Pathway: Triggers, Cytokines, and Genetic Factors

Psoriasis is a chronic inflammatory skin disorder driven by a complex interplay of immune dysfunction, genetic predisposition, and environmental triggers. It leads to excessive keratinocyte proliferation, resulting in red, scaly plaques. While not contagious, it significantly affects quality of life and is linked to systemic conditions such as psoriatic arthritis and cardiovascular disease.

Understanding psoriasis mechanisms is crucial for effective treatments. Researchers have identified key immune cells, cytokines, and genetic components that sustain the disease. Emerging evidence also suggests the microbiome may play a role. Exploring these factors provides insight into disease development and potential therapeutic strategies.

Triggers of the Psoriatic Pathway

Various external and internal factors contribute to psoriasis onset and exacerbation. Environmental stimuli such as physical trauma, infections, and medications can initiate or worsen lesions in genetically predisposed individuals. The Koebner response, where skin injury—cuts, burns, or scratching—induces localized inflammation, is a well-documented phenomenon. Mechanical stress activates keratinocytes to release pro-inflammatory mediators, fueling disease progression.

Microbial infections, particularly Streptococcus pyogenes, have been linked to psoriasis flares, especially guttate psoriasis, characterized by small, drop-like lesions. Molecular mimicry, where bacterial antigens resemble host proteins, triggers an immune response that mistakenly targets skin cells. Viral infections, including HIV, can also exacerbate psoriasis due to immune system dysregulation.

Certain medications interfere with skin cell turnover and inflammatory pathways, provoking or worsening psoriasis. Beta-blockers, lithium, and antimalarial drugs have been associated with new-onset or aggravated lesions. Abrupt corticosteroid withdrawal often leads to severe flare-ups. Some biologic therapies, used for other inflammatory diseases, have paradoxically induced psoriasis, underscoring the complexity of drug-related reactions.

Lifestyle factors such as smoking, alcohol consumption, and chronic stress influence psoriasis severity. Nicotine alters keratinocyte function and increases oxidative stress, promoting epidermal hyperproliferation. Excessive alcohol intake correlates with higher disease severity and reduced treatment efficacy, likely due to its impact on systemic inflammation. Psychological stress, while not a direct cause, exacerbates psoriasis by affecting skin barrier function and inflammatory signaling.

Immune-Driven Inflammatory Cascade

Psoriasis results from an immune-mediated inflammatory process that disrupts skin function. Activated immune cells sustain inflammation, promoting keratinocyte proliferation and plaque formation.

T Lymphocytes

T cells play a central role in psoriasis, particularly T helper (Th) cells. Th1 and Th17 cells are highly active in psoriatic lesions, producing cytokines that drive inflammation and keratinocyte hyperproliferation. Th17 cells secrete interleukin-17 (IL-17), which stimulates keratinocytes to release additional pro-inflammatory mediators, perpetuating the inflammatory cycle. IL-17 blockade has been shown to significantly reduce psoriatic symptoms.

Regulatory T cells (Tregs), which normally suppress excessive immune activation, are impaired in psoriasis. This imbalance allows pathogenic T cell subsets to dominate, sustaining chronic inflammation. Cytotoxic CD8+ T cells also infiltrate the epidermis, interacting with keratinocytes and contributing to tissue damage. The persistence of activated T cells, even in clinically resolved lesions, suggests psoriasis has long-term immunological memory, predisposing individuals to recurrent flare-ups.

Dendritic Cells

Dendritic cells (DCs) initiate and sustain the psoriatic immune response. Plasmacytoid dendritic cells (pDCs) release type I interferons (IFN-α and IFN-β), enhancing T cell activation. Myeloid dendritic cells (mDCs) produce tumor necrosis factor-alpha (TNF-α) and interleukin-23 (IL-23), crucial for sustaining Th17 cell activity. IL-23 promotes the expansion and survival of Th17 cells, making it a key target for monoclonal antibody therapies like guselkumab and risankizumab, which have shown significant efficacy.

Neutrophils

Neutrophils infiltrate psoriatic skin early, releasing reactive oxygen species (ROS) and neutrophil extracellular traps (NETs), which amplify inflammation by activating dendritic cells and recruiting T cells. Elevated NET formation has been observed in psoriatic lesions, suggesting a role in disease persistence.

Neutrophils also accumulate in the stratum corneum, forming Munro’s microabscesses, a histological hallmark of psoriasis. These microabscesses contain neutrophil-derived enzymes that degrade extracellular matrix components, worsening tissue damage. The presence of neutrophils correlates with disease severity, and therapies targeting neutrophil recruitment, such as IL-8 inhibitors, are being explored.

Key Cytokine Communication

Cytokines sustain psoriasis by driving inflammation and keratinocyte hyperproliferation. Among the most influential are interleukin-17 (IL-17), interleukin-23 (IL-23), and tumor necrosis factor-alpha (TNF-α).

IL-17, produced by Th17 cells, stimulates keratinocytes to release antimicrobial peptides and additional inflammatory mediators, reinforcing the inflammatory loop. Elevated IL-17 levels in psoriatic lesions correlate with disease severity, making it a prime therapeutic target. Monoclonal antibodies such as secukinumab and ixekizumab, which neutralize IL-17A, have shown efficacy in reducing plaque formation.

IL-23 sustains Th17 cell differentiation, ensuring persistent inflammation. Unlike IL-12, which promotes Th1 responses, IL-23 specifically drives pathogenic Th17 cell expansion. Genetic studies have linked IL-23 receptor (IL23R) polymorphisms to increased psoriasis susceptibility. Therapies targeting IL-23, such as guselkumab and risankizumab, disrupt the inflammatory cascade at an earlier stage and offer superior long-term efficacy.

TNF-α enhances cytokine production and promotes immune cell infiltration into the skin. It also stimulates keratinocyte proliferation, contributing to plaque formation. While TNF inhibitors like adalimumab and infliximab were among the first biologics approved for psoriasis, their efficacy varies, and they carry higher immunosuppression risks compared to IL-17 and IL-23 inhibitors. As a result, newer therapies focus on more selective cytokine blockade to minimize systemic side effects.

Keratinocyte Involvement

Keratinocytes, the predominant epidermal cells, exhibit abnormal proliferation and differentiation in psoriasis. In healthy skin, these cells mature and migrate to the surface over approximately 28 days. In psoriatic lesions, this process accelerates to three to five days, leading to an accumulation of immature keratinocytes and the formation of thick, scaly plaques. The disrupted differentiation process also alters lipid composition, impairing moisture retention and contributing to the dry, flaky appearance of psoriatic skin.

Keratinocytes further exacerbate psoriasis by producing proteins that sustain epidermal thickening. Keratin 16, typically expressed in response to skin injury, is persistently overproduced in psoriasis, reflecting chronic activation. Additionally, irregular expression of cornified envelope proteins compromises epidermal integrity, making the skin more susceptible to external irritants.

Genetic Influences

Genetic predisposition plays a significant role in psoriasis, with heritability estimates ranging from 60% to 90%. Over 60 susceptibility loci have been identified through genome-wide association studies (GWAS), with the strongest link found at the PSORS1 locus on chromosome 6, which harbors the HLA-C gene. The HLA-Cw6 allele is associated with a higher risk of developing psoriasis, particularly early-onset forms.

Beyond HLA-C, mutations in IL23R and TNIP1 enhance inflammatory signaling, fueling persistent immune activation. Polymorphisms in CARD14, a gene involved in NF-κB pathway regulation, have been linked to familial cases of plaque psoriasis. These genetic insights have informed targeted treatments, as biologics that inhibit IL-23 and TNF-α have demonstrated significant efficacy. While genetic factors alone do not trigger psoriasis, they establish a predisposed immune landscape that, when combined with environmental triggers, leads to disease onset.

Role of the Microbiome

The skin and gut microbiomes may influence psoriasis severity and treatment response. Dysbiosis, or microbial imbalance, has been observed in psoriatic patients, with bacterial diversity shifts correlating with disease activity. Studies using 16S rRNA sequencing show reduced Cutibacterium and Staphylococcus epidermidis, which contribute to skin barrier maintenance, alongside increased Streptococcus and Corynebacterium, which may promote inflammation.

Gut microbiome composition is also linked to psoriasis, with lower levels of beneficial Bacteroides species and an overrepresentation of Firmicutes in affected individuals. Since the gut and skin share immunological pathways, systemic inflammation from intestinal dysbiosis may contribute to psoriasis flares. Some clinical trials suggest probiotics could help restore microbial balance and improve symptoms, though further research is needed. Understanding the microbiome’s role in psoriasis opens new avenues for therapeutic modulation through diet, probiotics, and microbiota-targeted treatments.